The present invention relates to chemokine receptor antagonists, in particular, bicyclic diamine compounds that act as antagonists of chemokine CCR2 and CCR3 receptors including pharmaceutical compositions and uses thereof to treat or prevent diseases associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation.
The local production and secretion of a family of 8-10 KD chemotactic cytokines (called chemokines) mediate the local accumulation of inflammatory cells in many pathological inflammatory and autoimmune disease states. Chemokines have been found to be highly expressed in a variety of pathological states, including atherosclerosis, pulmonary fibrosis, asthma, psoriasis and rheumatoid arthritis, coinciding with the chronic macrophage accumulation of inflamed tissue (see, e.g., Barker, J. N., et al., J. Immunol., 146, 1192 (1991); Koch, A. E. J. Clin. Invest, 90, 772 (1996); Nelken, N. A., et al., J. Clin. Invest., 88, 1121 (1991); Gong, J. H., J. Exp. Med., 186, 131 (1997); Yla-Herttuala, S., et al., Proc. Natl., Acad. Sci., 88, 5252 (1991); Rovin, B. H., et al., Am. J. Kidney Dis., 31, 1065 (1998); and Gong, J. H. et al., J. Exp. Med., 186, 131 (1997)). Continuous local release of chemokines at sites of inflammation mediates the excessive migration of effector cells in chronic inflammation. Thus, blocking leukocyte recruitment to target tissues by inhibiting chemokine activity in inflammatory and autoimmune disease would be an effective therapeutic intervention.
The chemoattractant chemokines belong to a super family of pro-inflammatory mediators that promote the recruitment of multiple lineages of leukocytes and lymphocytes. The human chemokine polypeptides are 70-80 residues in length that share substantial sequence homology. These polypeptides share a common structural motif: a conserved set of four cysteine residues. Based on the position of the first two or four cysteine residues and the chromosomal location of the corresponding genes, two main chemokine families, CC and CXC, have been identified. Members of the CXC subfamily attract mainly neutrophils, except for platelet factor 4 (PF4) and gamma interferon inducible protein (IP10). The CC chemokines attract mainly monocytes, eosinophils, and lymphocytes but may also attract T lymphocytes. Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family that is a potent chemotactic and activating factor for monocytes and memory T cells. The other members of the of the CC chemokine family, MCP-2, MCP-3, MCP-4, MCP-5, macrophage inflammatory protein (MIP)-1xcex1, MIP-1xcex2, RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin also mediate chemotaxis in distinct but overlapping leukocyte subsets.
The molecular targets for chemokines are their cell surface receptors that belong to the seven-transmembrane helix (STH), G-protein coupled receptors. This type of receptor consists of a single polypeptide chain with an extracellular amino-terminal domain and a cytoplasmic-terminal domain. The amino terminal and the third extracellular domain are important for receptor ligand interaction. The third intracellular loop (50-75 amino acids long) interacts directly with G-proteins. At least five CC chemokine receptors have been identified (CCR1-CC R5) and all five CC receptors belong to the STH G-coupled protein receptor family. Each of these receptors mediates the binding and signaling of more than one chemokine. For example, the CCR1 receptor is specific for MIP-1 xcex1, RANTES, and MCP-3. CCR2B recognizes both MCP-1 and MCP-3; CCR3 is expressed on eosinophils and recognizes eotaxin; and CCR4 is found on basophils and responds to MIP1-xcex1, RANTES and MCP-1. The MCP-1 receptor CCR2b signals through multiple G-proteins including Gxcex1I, Gxcex1q, and Gxcex116. See, e.g., Monteclaro, F. S., J. Biol. Chem., 37, 23186 (1997). Thus, in addition to promoting the transmigration and emigration of circulating monocytes into tissues, MCP-1 interaction with the CCR2 receptor increases histamine release, calcium influx, cAMP activation, increases integrin expression and acts as a chemotactic factor for monocytes/macrophages. For further discussions, see Rollins, B. J., Blood, 78, 112 (1991); Neote, K., et al., Cell, 72, 415 (1993); Charo, I. F., et al., Proc Natl., Acad. Sci. USA, 91, 2752 (1994).
Various cell types including endothelial cells, smooth muscle cells, macrophages and fibroblasts produce MCP-1 and its murine homolog JE that was identified initially as a platelet-derived growth factor inducible gene. Although MCP-1 expression has been documented in a variety of human diseases that have inflammatory components, including atherosclerosis, multiple sclerosis, asthma and rheumatoid arthritis among many others, a direct cause and effect relationship has been difficult to prove. MCP-1 along with many other chemokines is expressed in many inflammatory lesions. Direct injection of MCP-1 into rodent""s skin provides only a mild infiltrate or no infiltrate at all. See, Zachariae, C. O., J. Exp. Med., 171, 2177 (1990). However, MCP-1 has been demonstrated to play a role in atherosclerosis. Overexpression of MCP-1 by macrophages in apolipoprotein E deficient mice increases monocytic infiltration and atherosclerosis. See, Aiello, R. J., et al., Arteriosclero Thromb Vasc Biol., 19, 1518 (1999). Several studies using MCP-1 transgenic mice have suggested that the ability of MCP-1 to elicit monocyte infiltration depends on MCP-1 being expressed at specific sites. See, Fuentes, M. E., J. Immunology, 155, 5769 (1995). Recently MCP-1 deficient mice and MCP-1 receptor (CCR2) deficient mice were shown to have decreased atherosclerotic lesion formation. See, Boring, L. Nature, 394, 894 (1998).
Leukocyte entry into tissue involves a cascade of molecular events including chemotactic signaling to circulating cells, interaction with endothelial cells and transmigration through tissues. Significant advances have been made in the identification of leukocyte adhesion molecules and their cellular and extracellular matrix legends. Leukocyte-endothelial interactions occur in several phases which include rolling, firm adhesion and transmigration. See, Traffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigm; Springer, Cell, 76,301 (1994). Primarily a specific class of adhesion molecules mediates each of the phases of adhesion. Integrins are one of the specific classes and exist as heteromeric-cell surface proteins. Recent cell culture studies have shown that the expression of monocyte chemokines MCP-1, MIP-1 xcex1, and RANTES increases the expression of the xcex1 chain of 2 members of the xcex22 family of integrins, CD11a and CD11b. CD11b (one of two subunits of the CD11b/CD18 (Mac-1, CR3 receptor) xcex22 integrin) is highly regulated and is expressed maximally in terminally differentiated myeloid cells. See, Corbi, A. J., Biol. Chem, 263, 12403 (1988). Additionally MCP-1 has been reported to selectively activate the xcex21 integrin family of leukocyte molecules, suggesting a role in leukocyte adhesion. See, Woldemar, et al., Immunity, 4, 179 (1996). Thus, in addition to acting as a chemoattractant, MCP-1 may further potentiate the inflammatory response by promoting integrin expression and cellular adhesion.
Chemoattractants appear to be required for the transendothelial migration both in vivo and in vitro and can induce many of the steps required for transmigration in vivo. MCP-1 is also abundantly expressed at the sites of inflammation, antigen challenge and autoimmune diseases and is an excellent candidate to inhibit tissue trafficking of monocytes during inflammation and autoimmune diseases. Therefore, compounds which inhibit the binding of MCP-1 to the chemokine CCR2 receptor (MCP-1 receptor antagonists) provide useful leads for drugs that will inhibit the action of MCP-1 on target cells.
PCT publications WO 97/44329; WO 99/25686; WO 00/07678; WO 99/07351; WO 99/09984; WO 00/31032; WO 00/35452; WO 99/32468; WO 00/69820; WO 00/69815; and WO 00/69848; WO 00/46195; WO 00/46196; WO 00/46197; WO 00/46198 and WO 00/46199 describe classes of cyclic amines and cyclic diamines which reportedly modulate chemokine receptor activity.
Homing and activation of eosinophils, basophils, and memory CD4+ Th2+ lymphocytes in lung tissues are considered important to the etiology of chronic airway inflammatory diseases. These cells most likely orchestrate asthmatic and allergic responses by secreting leukotrienes, histamine, and pro-inflammatory Th2 cytokines such as GM-CSF, IL-3, IL-4, IL-5 and IL-13. Further evidence for the role of Th2 cytokines comes from studies with atopic asthmatics where bronchial cytokine expression correlates with the patient""s baseline FEV1, histamine PC20, serum IgE levels, and disease severity. Studies in animal asthma models also support a causative role of eosinophils, basophils and Th2 cells in disease induction (see, Rothenberg, M. E., Am. J. Respir. Cell Mol. Biol., 21, 291 (1999)).
Many chemokines have been shown to mediate the recruitment and activation of eosinophils, basophils and Th2+ cells, which express several chemokine receptors during different stages of cell differentiation and/or activation. For example, eotaxin, eotaxin 2, MCP-3, MCP-4, and RANTES, which are produced from human lung mast cells, epithelial cells and to macrophages as well as circulating leukocytes, activate eosinophils, basophils and Th-2 cells through binding to the cell surface receptor CCR3. See, Kitaura, M., et al., J. Biol. Chem., 271, 7725 (1996) and Corrigan, C., Current Opinion Invest. Drugs, 1, 321 (2000). Although they differ in potency, they have a very similar range of biological actions. See, Griffiths, J. D. et al., Biochem. Biophys. Res. Commun., 197, 1167 (1993); Jose, P. J. et al., J. Exp. Med., 179, 881 (1994); and Rothenberg, M. E., New England J. Med., 338. 1592 (1998). Eotaxin levels are elevated in induced sputum of atopic asthmatics compared with normal controls. See, Yamada, H. et al., Allergy, 54, 730 (1999). Nasal challenge of eotaxin causes airway eosinophil infiltration and activation, and produces clinically symptomatic inflammatory responses in humans. See, Hanazawa, T. et al., J. Allergy Clin. Immunol., 105, 58 (1999). Animal model studies also demonstrate that the biological activity of eotaxin is involved in selective infitration of eosinophils into lungs. In addition, the antibody against eotaxin and CCR3 partially reduces antigen-induced pulmonary eosinophilia in a guinea pig model of allergic asthma. See, Sabroe, I., et al., J. Immunol., 161, 6139 (1998). Similar to the anti-eotaxin treatment, knockout of CCR3 shows reduced pulmonary infiltration of eosinophils in allergic mice. Hence, antagonists of CCR3 provide useful compound leads for the treatment of chronic inflammatory diseases such as allergy and asthma.
The present invention provides a novel class of bicyclic amine compounds that act as antagonists of chemokine receptors, in particular CCR2 and CCR3 receptors. The bicyclic amine compounds of the present invention include the following compounds of Formula (I): 
wherein
A is a substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C2-C6)alkenyl, substituted or unsubstituted partially saturated or fully saturated (C3-C6)cycloalkyl, substituted or unsubstituted partially saturated or fully saturated 5 to 6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;
a is 0, 1, 2 or 3;
w, x, y and z are each independently 0, 1, 2, 3 or 4, with the proviso that (i) x is not 0 when w is 0; (ii) y is not 0 when z is 0; (iii) x is not 0 when w is 1, y is 0 and z is 1; (iv) x is not 0 when w is 1, z is 0 and y is 1; (v) x is not 0 when y is 0; (vi) w is not 0 when z is 0; (vii) w+x is less than 8; and (viii) y+z is less than 8;
p is 0 or 1;
L is a linking group selected from the group consisting of xe2x80x94(CH2)qxe2x80x94Xxe2x80x94, where X is NH, O, or oxo (i.e., keto) and q is an integer from 1 to 4,xe2x80x94S(O)rxe2x80x94(CH2)txe2x80x94NHxe2x80x94, where r is 0, 1 or 2 and t is an integer from 1 to 4, -(aryl)-NHxe2x80x94 (i.e., The aryl group is attached to the nitrogen of the bicyclic diamine and the xe2x80x94NHxe2x80x94 group is attached to B. The aryl group may also contain additional substituents on the aromatic ring.), -(heteroaryl)-NHxe2x80x94 (i.e., The heteroaryl group is attached to the nitrogen of the bicyclic diamine and the xe2x80x94NHxe2x80x94 group is attached to B. The heteroaryl group may also contain additional substituents on the heteroaromatic ring), and an amino acid residue where the amino nitrogen of the amino acid residue is attached to B and the carbonyl of said amino acid residue is attached to the ring nitrogen; and
B is a substituted or unsubstituted (C1-C6)alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted (C1-C6)alkoxy-carbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted (C1-C6)alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted (C1-C6) alkylthiocarbonyl, substituted or unsubstituted arylthiocarbonyl, substituted or unsubstituted (C1-C6)alkyl-carbamoyl, substituted or unsubstituted arylcarbamoyl, substituted or unsubstituted (C1-C6)alkyl-C(xe2x95x90NH)xe2x80x94, substituted or unsubstituted aryl-C(xe2x95x90NH)xe2x80x94, or a protecting group (Pg);
a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound or the prodrug.
An example of an amino acid residue is a unit having the following formula 
where the xcex1-amino nitrogen of said amino acid residue is attached to B;
R1 and R2 are each independently hydrogen, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C2-C6)alkenyl, substituted or unsubstituted partially saturated or fully saturated (C3-C6)cycloalkyl, substituted or unsubstituted partially saturated or fully saturated 5 to 6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group; or R1 or R2 is taken together with R3 to form a 5 to 6 membered ring; or R1 and R2 is taken together to form a 3 to 6 membered ring; and
R3 is hydrogen, taken together with a substituent of B forms a substituted or unsubstituted five or six membered partially saturated or fully saturated heterocyclic ring (e.g., pyrrolidine, pyrazole, imidazole, imidazoline, imidazolidine, morpholine, butyrolactam, valerolactam, piperidine, piperazine, imidazolidinone, phthalimide, and hydantoin), or taken together with R1 or R2 forms a 5 to 6 membered ring.
Preferred compounds of formula (I) are those where A is selected from (C1-C6)alkyl, (C2-C6)alkenyl, partially saturated or fully saturated (C3-C6)cycloalkyl, partially saturated or fully saturated 5 to 6 membered heterocyclic ring, aryl, or heteroaryl group, wherein each of these groups are unsubstituted or substituted with one or more groups (preferably 1, 2 or 3 groups) each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C1-C6)alkoxy, aryloxy, sulfhydryl (mercapto), (C1-C6)alkylthio, arylthio, mono- and di-(C1-C6)alkyl amino, quaternary ammonium salts, amino(C1-C6)alkoxy, hydroxy(C1-C6)alkylamino, amino(C1-C6)alkylthio, cyanoamino, nitro, carbamyl, keto (oxy), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy, and combinations thereof; a is 1; w and x are 0, 1 or 2; z and y are 0 or 1; p is 1; and L is 
where R3 is hydrogen and R1 and R2 are each indepedently selected from hydrogen and C1-C6 alkyl; and B is selected from (C1-C6)-alkylcarbonyl, arylcarbonyl, (C1-C6)alkoxy-carbonyl, aryloxycarbonyl, (C1-C6)alkylsulfonyl, arylsulfonyl, (C1-C6) alkylthiocarbonyl, arylthiocarbonyl, (C1-C6)alkyl-carbamoyl, arylcarbamoyl, (C1-C6)alkyl-C(xe2x95x90NH)xe2x80x94, and aryl-C(xe2x95x90NH)xe2x80x94, wherein each of these groups are unsubstituted or substituted with one or more groups (preferably 1, 2, or 3 groups) each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C1-C6)alkoxy, aryloxy, sulfhydryl (mercapto), (C1-C6)alkylthio, arylthio, mono- and di-(C1-C6)alkyl amino, quaternary ammonium salts, amino(C1-C6)alkoxy, hydroxy(C1-C6)alkylamino, amino(C1-C6)alkylthio, cyanoamino, nitro, carbamyl, keto (oxy), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy, and combinations thereof.
More preferred compounds of formula (I) are those where A is selected from (C1-C6)alkyl, (C2-C6)alkenyl, partially saturated or fully saturated (C3-C6)cycloalkyl, partially saturated or fully saturated 5 to 6 membered heterocyclic ring, aryl, or heteroaryl group, wherein each of these groups are unsubstituted or substituted with one or more R1a groups (preferably 1, 2, or 3 R1a groups) each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy and aryl(C1-C6)alkoxy (e.g., benzyloxy); a is 1; (i) w, x, z and y are 1,(ii) w is 2, x is 0, and z and y are 1, (iii) w is 0, x is 2, and z and y are 1, (iv) w, x and y are 1, and z is 0; or (v) w, x, and z are 1, and y is 0; p is 1; L is xe2x80x94(CH2)qxe2x80x94C(xe2x95x90O)xe2x80x94, where q is an integer from 1 to 4; and B is selected from (C1-C6) alkylcarbonyl, arylcarbonyl, (C1-C6)alkoxy-carbonyl, aryloxycarbonyl, (C1-C6)alkylsulfonyl, arylsulfonyl, (C1-C6) alkylthiocarbonyl, arylthiocarbonyl, (C1-C6)alkyl-carbamoyl, arylcarbamoyl, (C1-C6)alkyl-C(xe2x95x90NH)xe2x80x94 and aryl-C(xe2x95x90NH)xe2x80x94, wherein each of these groups are unsubstituted or substituted with one or more R1b groups (preferably 1, 2, or 3 R1b groups) each independently selected from halo, C1-C6 alkyl, halo(C1-C6)alkyl (e.g., trifluoromethyl), C1-C6 alkoxy, halo(C1-C6)alkoxy (e.g., trifluoromethoxy, difluoromethoxy and the like), amino, amido (e.g., acetamido), nitro, aryloxy (e.g., phenoxy) and C1-C6 alkylthio (e.g., methylthio, ethylthio and the like).
Even more preferred are those compounds of formula (I) where A is aryl or heteroaryl, unsubstituted or substituted with one or more R1a groups (preferably, 1, 2, or 3 R1a groups) each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy and aryl(C1-C6)alkoxy (e.g., benzyloxy); and B is selected from (C1-C6)alkylcarbonyl and arylcarbonyl, wherein each of these groups are unsubstituted or substituted with 1, 2, or 3 R1b groups each independently selected from halo, C1-C6 alkyl, halo(C1-C6) alkyl (e.g., trifluoromethyl), C1-C6 alkoxy, halo(C1-C6)alkoxy (e.g., trifluoromethoxy, difluoromethoxy and the like), amino, amido (e.g., acetamido), nitro, aryloxy (e.g., phenoxy) and C1-C6 alkylthio (e.g., methylthio, ethylthio, and the like).
Most preferred compounds of formula (I) are those compounds where A is phenyl, unsubstituted or substituted with 1, 2, or 3 R1a groups each independently selected from hydrogen, halo, C1-C6 alkyl, and C1-C6 alkoxy.
In a preferred embodiment of the present invention, compounds of Formula (IA) below are provided: 
wherein
R1a for each occurance is independently hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, aryl(C1-C6)alkoxy (e.g., benzyloxy), or two adjacent R1a groups taken together form a substituted or unsubstitued carbocyclic, heterocyclic, aromatic or heteroaromatic 5 to 6 membered fused ring;
m is 0, 1, 2, 3, 4, or 5 (preferably 3 or less);
R1 and R2 are each independently hydrogen, C1-C6 alkyl, aryl(C1-C6)-alkyl (e.g., benzyl), or R1 and R2 is taken together to form a 3 to 6 membered ring, or R1 or R2 is taken together with R3 to form a five- or six-membered ring;
R3 is hydrogen, taken together with R1b forms a substituted or unsubstituted five or six membered partially saturated or fully saturated heterocyclic ring, or taken together with R1 or R2 form a five- or six-membered ring;
R1b for each occurance is independently hydrogen, halo, C1-C6 alkyl, halo(C1-C6)alkyl (e.g., trifluoromethyl), C1-C6 alkoxy, halo(C1-C6)alkoxy (e.g., trifluoromethoxy, difluoromethoxy and the like), amino, amido (e.g., acetamido), nitro, aryloxy (e.g., phenoxy), C1-C6 alkylthio (e.g., methylthio, ethylthio and the like), taken together with R3 forms a substituted or unsubstituted five or six membered partially saturated or fully saturated heterocyclic ring, or two adjacent R1b substituents taken together form a substituted or unsubstitued carbocyclic, heterocyclic, aromatic or heteroaromatic 5 to 6 membered fused ring; and
n is 0, 1, 2, 3, 4 or 5 (preferably 3 or less);
a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound or the prodrug.
Preferred compounds are those where R1a is methyl or chloro; m is 2; R1 is hydrogen; R2 is hydrogen; R3 is hydrogen, R1b is methyl, trifluoromethyl, amino, iodo, bromo, chloro or nitro; and n is 1 or 2; a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound or the prodrug.
Also preferred are the following compounds:
N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide;
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide;
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide;
2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide;
3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of the compound or the prodrug.
Each of the compounds described herein contain at least one chiral center; consequently, those skilled in the art will appreciate that all enantiomers and/or diasteroisomers of the compounds disclosed and discussed herein are within the scope of the present invention. However, when the bicyclic rings are 4- or 5-membered rings, then the fused rings are preferably in the cis configuration.
Compounds of Formula I above are useful chemokine receptor antagonists; therefore, another embodiment of the present invention is a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I (including prodrugs thereof, and pharmaceutically acceptable salts, hydrates, and/or solvates of the compounds or the prodrugs) and a pharmaceutically acceptable excipient, diluent or carrier.
In yet another embodiment of the present invention, a method for treating or preventing diseases associated with monocyte and/or lymphocyte accumulation is provided which comprises administering a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention) to an animal in need thereof. The method is useful for treating or preventing diseases such as atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, wound healing, Crohn""s disease, encephalomyelitis and transplant rejection in animals, in particular mammals including humans. Accordingly, the compounds of the present invention may be used in the manufacture of a medicament for the treatment or prevention of diseases associated with monocyte and/or lymphocyte accumulation.
In a preferred embodiment, a compound of Formula (1B) 
where x, y, z, w, L, p and B have the same meaning as described above for compounds of Formula (I) (including prodrugs thereof and pharmaceutically acceptable salts, hydrates and solvates of the compounds and the prodrugs) is administered to an animal in need of treatment.
Preferred compounds for inhibition of binding to CCR2 receptors include the following:
N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide;
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide;
2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and
3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of the compound or the prodrug.
In yet another aspect of the present invention, a pharmaceutical kit for use by a consumer having or at risk of having a disease or condition such as atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, wound healing, Crohn""s disease, encephalomyelitis and transplant rejection in animals, is provided. The kit comprises a) a suitable dosage form comprising a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of the compound or the prodrug; and b) instructions describing a method of using the dosage form to treat or prevent diseases associated with monocyte and/or lymphocyte accumulation.
Compounds of the present invention are also useful as antagonists of eotaxin 2, MCP-3, MCP-4, and RANTES binding to the CCR3 receptor; therefore, another embodiment of the present invention is a method for treating or preventing diseases associated with leucocyte accumulation is provided which entails administering a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition described above) to an animal in need thereof. The method is useful for treating or preventing chronic inflammatory diseases such as allergy and asthma, including but not limited to allergic rhinitis, eczema and atopic dermatitis in animals (preferably humans). Accordingly, the compounds of the present invention may be used in the manufacture of a medicament for the treatment or prevention of diseases associated with leucocyte accumulation.
In a preferred embodiment, a compound of Formula (1C) 
where x, y, z, w, L, p and B have the same meaning as described above for compounds of Formula (I) (including prodrugs thereof and pharmaceutically acceptable salts, hydrates and solvates of the compounds and the prodrugs) is administered to an animal in need of such treatment.
Preferred compounds for inhibition of binding to CCR3 receptors include the following:
3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl)-benzamide;
3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
3-chloro-N-(2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl)-benzamide; and
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide; a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of the compound or prodrug.
In yet another aspect of the present invention, a pharmaceutical kit for use by a consumer having or at risk of having a disease or condition resulting from a chronic inflammatory diseases such as allergy and asthma is provided. The kit comprises a) a suitable dosage form comprising a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of the compound or the prodrug; and b) instructions describing a method of using the dosage form to treat or prevent diseases associated with leucocyte accumulation.
The compounds of the present invention may also be used in conjunction with at least one other pharmaceutical agent for the treatment or prevention of diseases/conditions described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include nutraceuticals, cholesterol absorption inhibitors, HMG-CoA reductase inhibitors, MTP/Apo B secretion inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase transcription inhibitors, HMG-CoA reductase translation inhibitors, CETP inhibitors, squalene synthetase inhibitors, squalene epoxidase inhibitors, squalene cyclase inhibitors, combined squalene epoxidase/squalene cyclase inhibitors, ACAT inhibitors, lipase inhibitors (including pancreatic lipase inhibitors and gastric lipase inhibitors), peroxisome proliferator-activated receptor (PPAR) agonists, nonsteroidal anti-inflammatory drugs (NSAIDS) and cyclooxygenase enzyme inhibitors (COX-2 inhibitors). Therefore, a method is provided for treating or preventing a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation which comprising administering to a mammal in need of such treatment a compound of the present invention and at least one of the pharmaceutical agents described above.
The combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the present invention, at least one of the pharmaceutical agents described above and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof, and (ii) a second composition comprising at least one of the pharmaceutical agents described above and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof. The pharmaceutical compositions may be administered simultaneously or sequentially and in any order.
In yet another embodiment of the present invention is a pharmaceutical kit comprising: a) a compound of the present invention, and a pharmaceutically acceptable carrier, excipient or diluent in a first unit dosage form; b) a pharmaceutical agent selected from the group consisting of a nutraceutical, a cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor. a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor, and a pharmaceutically acceptable carrier, excipient or diluent in a second unit dosage form; and c) a container.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to a hydrocarbon radical of the general formula CnH2n+1. The alkane radical may be straight or branched. For example, the term xe2x80x9c(C1-C6)alkylxe2x80x9d refers to a monovalent, straight, branched, or cyclic aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like). The alkane radical may be unsubstituted or substituted with one or more substituents defined below. For example, a xe2x80x9chaloalkylxe2x80x9d refers to an alkyl group substituted with one or more halogen atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, and the like). Similarly, the alkyl portion of an alkoxy, alkylamino, dialkylamino, or alkylthio group have the same definition as above.
The term xe2x80x9cpartially saturated or fully saturated cycloalkylxe2x80x9d or xe2x80x9cpartially saturated or fully saturated heterocyclic ringxe2x80x9d refers to nonaromatic rings that are either partially or fully hydrogenated. For example, partially or fully saturated cycloalkyl includes groups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Partially saturated or fully saturated heterocyclic rings include groups such as dihydropyridinyl, pyrrolidinyl, (2-, 3- or 4)-N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidyl, imidazolyl, imidazolidyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, morpholino, thiomorpholino, tetrahydrothienyl, and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon containing at least one carbon-carbon double bond. As described above for alkyl, the alkene radical may be straight or branched and the alkene radical may be unsubstituted or substituted with one or more substituents defined below.
The term xe2x80x9carylxe2x80x9d refers to aromatic moieties having single (e.g., phenyl) or fused ring system containing 6 to 14 carbon atoms (e.g., naphthalene, anthracene, phenanthrene, etc.). The aryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) defined below. Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.) The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic moieties containing at least one heteroatom (preferably, 1, 2, 3 or 4 heteratoms, more preferably 1 or 2 heteroatoms) within the aromatic ring system which may be the same or different (e.g., pyrrole, pyridine, indole, thiophene, furan, benzofuran, imidazole, pyrimidine, purine, benzimidazole, quinoline, etc.). The heteroatoms in the ring system are generally selected from oxygen, sulfur, nitrogen or combinations thereof. The aromatic moiety may consist of a single or fused ring system containing 5 to 14 members. The heteroaryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) defined below.
The term xe2x80x9camino acid residuexe2x80x9d refers to a structural unit of a natural, modified or unusual amino acid (as defined herein) remaining after the loss of a hydroxy group from the carboxylic acid group and the loss of a hydrogen from the amino group. For example, a residue of valine would have the following structure; 
The term xe2x80x9csubstitutedxe2x80x9d specifically envisions and allows for substitutions which are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament. Suitable substituents for any of the groups defined above include alkyl, alkenyl, aryl, heteroaryl, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, alkoxy, aryloxy, sulfhydryl (mercapto), alkylthio, arylthio, mono- and di-alkyl amino, quaternary ammonium salts, aminoalkoxy, hydroxyalkylamino, aminoalkylthio, cyanoamino, nitro, carbamyl, keto (oxy), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy, and combinations thereof.
The term xe2x80x9cprotecting groupxe2x80x9d or xe2x80x9cPgxe2x80x9d refers to a substitutent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, an xe2x80x9camino-protecting groupxe2x80x9d is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a xe2x80x9chydroxy-protecting groupxe2x80x9d refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include acetyl and silyl. A xe2x80x9ccarboxy-protecting groupxe2x80x9d refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include xe2x80x94CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
The term xe2x80x9csolvatexe2x80x9d refers to a molecular complex of a compound represented by Formula I (including prodrugs and pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term xe2x80x9chydratexe2x80x9d refers to the complex where the solvent molecule is water.
The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of a compound of the present invention that attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the animal being treated therewith.
The term xe2x80x9canimalxe2x80x9d refers to humans, companion animals (e.g., dogs, cats and horses), food-source animals (e.g., cows, pigs, sheep and poultry), zoo animals, marine animals, birds and other similar animal species.
The term xe2x80x9ccompounds of the present inventionxe2x80x9d refers to compounds of Formula (I), prodrugs thereof, and pharmaceutically acceptable salts, hydrates and/or solvates of the compounds and/or prodrugs, as well as, all stereoisomers (including diastereomers (except trans configurations of four and five members fused rings that are unstable) and enantiomers), tautomers and isotopically labelled compounds.